The overall goal of this research program is to understand physiologic regulation of microvascular permeability, an important determinant of nutrient delivery to tissues. Nitric oxide (NO) is a major regulator of local blood flow and pressure; recent studies support a role of NO in regulation of permeability. Determining how NO regulates permeability is complicated by recent data from this laboratory that challenge the traditional models of vascular transport pathways. The data reveal that while NO can modify flux of volume and of the serum protein, albumin, transport of albumin may occur through selective pathways that contribute little to movement of water and other solutes. A novel approach will be used to determine whether selective albumin transport occurs in vivo, basally and upon stimulation with NO and cyclic guanosine monophosphate (cGMP, a downstream signaling molecule for NO). The data also support that NO may interact with blood elements in regulation of permeability. Three aims will address unresolved questions of how NO regulates permeability: 1) Which vascular transport pathways are regulated by NO and cGMP? We hypothesize that NO and cGMP enhance volume and solute flux through convective pathways, without affecting selective albumin transport. 2) Which cell signaling mechanisms are responsible for regulation of solute transport pathways by NO? We hypothesize that NO enhances microvascular convective solute flux by acting through cGMP and cGMP-dependent protein kinase. 3) Which blood cells interact with NO in regulation of permeability? We hypothesize that neutrophils, and not platelets, mediate microvascular permeability responses to NO. Broader knowledge of physiologic regulation of microvascular permeability will help understand pathologic alterations in permeability in conditions such as sepsis, acute respiratory distress syndrome and ischemia-reperfusion injury. The long-term goal is to apply the knowledge gained from these studies to allow optimal management of patients with these important clinical entities and their associated microvascular alterations.